Severe viral diseases are caused by a combination of virus-mediated cytopathic effects and either an acutely overactive or chronic inflammatory response. Diseases, such as keratoconjunctivitis by HSV1 or Adenovirus, encephalitis by HSV2 (in neonates) or West Nile virus, and emerging pandemic diseases, such as SARS and influenza, frequently cause severe complications and disabilities. These include blindness, severe mental retardation, pneumonia, acute respiratory distress and even death. Current therapies, when available, rely almost entirely on virus-specific antiviral drugs. However, elimination of the virus by antivirals does not prevent the inflammatory complications that result ultimately in disease manifestations. Therefore, corticosteroids are often used when inflammatory complications ensue. Corticosteroids, however, frequently lead to increased viral replication or reactivation of latent virus, thereby resulting in a difficult to interrupt vicious ycle. No single drug currently exists that can both inhibit viral replication and control deleterious inflammation. Our data, however, support a paradigm shifting hypothesis where simple and achievable metabolic changes in the tissue microenvironments can concurrently inhibit viral replication, modulate the inflammatory and angiogenic responses, and promote tissue healing, while allowing the development of a protective immune response. The depletion of the amino acids arginine or tryptophan by the enzymes arginase 1 (Ase-1) and indoleamine 2,3- dioxygenase (IDO) is one of the mechanisms by which the immune system regulates the magnitude of its response and prevents collateral damage to normal tissues during inflammation. It is also a mechanism frequently hijacked by tumors to escape an anti-tumor immune response. Here, we show that the in vivo depletion of a single amino acid has a potent and unexpected therapeutic effect in treating severe viral diseases. Arginine depletion inhibited a broad range of viral replication and promoted healing of tissues, while concurrently modulating deleterious inflammation and disease-associated neovascularization. This paradigm shifting observation leads us to propose that understanding the immunological and molecular pathways by which this therapeutic process occurs will not only create a new understanding of the metabolic mechanisms operating during severe viral and inflammatory diseases, but also create a platform for the development of novel therapies utilizing these natural immunoregulatory pathways.
Severe viral diseases such as infections of the cornea by Herpes virus and adenovirus, encephalitis by West Nile virus, and pandemic influenza cause serious complications and frequently result in permanent disabilities. The disease is caused by the combined effect of the viral infection and an overactive immune response and current anti-viral drugs do not always prevent the damaging effects of the disease. Therefore, it is important to find a treatment that can inhibit the growth of the virus and control inflammation while allowin for the development of protective and long lasting immunity;simple and achievable metabolic changes can provide both effects and promote healing of the tissues.
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